OBJECTIVE: The relatively modest benefit of vasomotor symptom relief in clinical trials of isoflavones may reflect once-daily dosing and low percentages of participants who are able to metabolize daidzein into equol, a potentially more biologically active isoflavone. This pilot study examined whether symptom reduction was greater with more frequent administration and with higher daily doses. In addition, we explored possible effect modification by equol producer status. METHODS: We randomized 130 perimenopausal (no menses in the past 3 mo) and postmenopausal (≥12 mo of amenorrhea) women with a mean of five or more moderate/severe hot flashes per day to treatment arms with varying total daily isoflavone doses and dosing frequency, separately for equol producers and nonproducers. Participants recorded the daily frequency and severity of hot flashes. Analyses compared mean daily hot flash intensity scores (sum of hot flashes weighted by severity) by total daily dose and by dosing frequency. Dose-and frequency-related differences were also compared for equol producers and nonproducers. RESULTS: Hot flash intensity scores were lowest in women randomized to the highest total daily dose (100-200 mg) and in women randomized to the highest dosing frequency (twice daily to thrice daily), with greater benefits on nighttime scores than on daytime scores. Dose-and frequency-related differences were somewhat larger in equol producers than in nonproducers. CONCLUSIONS: These results suggest that a twice-daily to thrice-daily dosing frequency may improve the benefit of isoflavones for vasomotor symptom relief, particularly in equol producers and for nighttime symptoms. Larger studies are needed to confirm these findings. © 2013 The North American Menopause Society.